Head-on collisions of proteins create mutations

And the genomes of bacteria have evolved to take advantage of this.

One of the central tenets of evolutionary theory is that mutations are random—you can't predict what the next one will be, or when it's going to happen. But it also turns out that mutations are probabilistic. Some of them are a bit more or less likely, depending on the chemistry of the DNA base and its location in the genome.

Now, researchers have identified a mechanism that makes certain types of mutation more probable. This mechanism is a head-on collision between proteins that involves the complex that copies DNA when a cell divides. Because of the mechanics of these collisions, there's a distinct bias towards mutations occurring on one of the two strands of DNA that make up a double helix. The researchers found that this bias is so fundamental that bacterial genes are arranged to take advantage of it, so that some key genes are kept safer from mutations, while others that are key to adaptation can mutate more often.

The problem with collisions arises from the structure of DNA itself. The sugars in the molecule's backbone have a distinctive top (the 5' carbon) and bottom (the 3' carbon). Even in a molecule that's millions of sugars long, every single one of those is oriented the same way. If you move down the strand in one direction, you'll always hit the 5' end first (if you go in the other direction, you'll always hit the 3' end).

This orientation pervades the chemistry of the enzymes that copy DNA, either into a duplicate DNA molecule or into RNA. Every single one that we know about operates in the 5' to 3' direction. (This is thought to be a result of evolution having only managed to make a good copying enzyme once; every one in existence today is just a modified version of that original enzyme.) So, if you started in one place and tried to copy both DNA strands at once, you'd have to send the copying proteins in opposite directions from your start point.

But life doesn't actually do this. In order to coordinate the copying of both strands, one set of copying proteins sets off in the usual direction. But the other DNA strand gets looped around before being fed to a linked enzyme, and copied in small chunks. This may be hard to envision but, conveniently, someone's done the hard work of envisioning it for you.

DNA replication. Note that while one protein complex moves straight down the DNA, the other has to work hard to copy the opposite strand in smaller chunks.

So, why might this be a problem? The enzyme copying DNA isn't the only thing doing so in the cell—the ones that transcribe it to RNA may be working at the same time. If they're working on the strand that moves in the normal direction, they and the DNA copying proteins will both be heading the same way, which doesn't create much of a problem. But if the transcription proteins are working on the other, looped around strand, the whole complex can slam into it in a head-on collision.

The researchers showed that these head-ons have consequences. They stuck a gene into the chromosome and found that, with the transcription enzymes shut down, mutation rates were identical on both of the two DNA strands. When transcription was switched on, the mutation rate more than doubled. Presumably, the collisions interfere with the proteins copying DNA, causing them to make mistakes more often.

To check the consequence of this, the researchers identified a set of what they called "core genes," which were present in all of the isolates of their bacteria (called B. subtilis) and had very few sequence differences, all of which indicate they perform very important functions. Over 80 percent of these turned out to be encoded on the strand that is less prone to mutations from collisions. The 17 percent left on the other strand? They picked up significant mutations at a rate 43 percent higher than the ones on the safe strand.

If these genes are so important, you may be asking, why are any left on the mutation-prone strand? The authors noticed that the functions of the genes present there tended to be involved in the bacteria's stress response. Being able to adapt more rapidly to changing conditions when under stress can have obvious advantages.

So, overall, it looks like the bacteria's genomes are arranged to optimize a known source of mutations. Most important genes that can't tolerate mutations well are kept on a DNA strand where they're less prone to getting any. The few where changes can be useful are arranged so they suffer mutations more often. It's important to note, though, that this evolutionarily favorable arrangement can be the product of evolution itself. Rearrangements of the genome happen all the time; if any of them happen to be useful, they'll spread through the population. And "useful" can certainly include having a gene avoid (or get) mutations more often.

Promoted Comments

It's so cool that natural selection can search the ENTIRE design space spanned by variation in parallel, including going meta. Which is what is going on when evolution selects for designs that can more easily evolve. You're selecting not for first-order things like disease resistance etc, but for highly abstract high-order things like "is structured in such a way that subsequent evolution is more likely to produce fit variants".

The amazing act of evolution and adaptation. If you only have a right hand you learn to bend and stretch in odd ways to scratch all the parts of your body. It's far easier with a left hand. One wonders what could be accomplished if we ever get good enough at engineering at this level to simply add an enzyme that can transcode backwards. Granted, our first 1e9 trials aren't going to be all that successful but we'll be able to take large steps for which there would be no neutral or advantageous reason to propagate a trait other than the contrived environment we place our creations in for a specific purpose.

Hey Lamarck, hows it goin'? Do you feel sore about the bad rap everyone has seemed so enamored of throwing your way? I always liked ya'.

Sorry, there's nothing Lamarkian about this.

Quoting from the article:

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If these genes are so important, you may be asking, why are any left on the mutation-prone strand? The authors noticed that the functions of the genes present there tended to be involved in the bacteria's stress response.

Seems Lamarckian enough. I understand that there would need to then be a mechanism for inheriting these mutations. Which, since bacteria exchange genes, is sort of like it.

It's so cool that natural selection can search the ENTIRE design space spanned by variation in parallel, including going meta. Which is what is going on when evolution selects for designs that can more easily evolve. You're selecting not for first-order things like disease resistance etc, but for highly abstract high-order things like "is structured in such a way that subsequent evolution is more likely to produce fit variants".

Evolution - shuffling its cards way before your grandparents learned how to.

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if the transcription proteins are working on the other, looped around strand, the whole complex can slam into it in a head-on collision.

In case anyone else got confused here, I found this paper with a figure of head-on replication transcription collisions helpful - they happen upstream the replication site of the two anti-parallel DNA strands. [ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149691/ , fig 1]

Apparently the transcription mechanism doesn't work on the single strands, I assume because it has to separate the strands partially to get started. And the downstream DNA already counts as two separate strings.

If these genes are so important, you may be asking, why are any left on the mutation-prone strand? The authors noticed that the functions of the genes present there tended to be involved in the bacteria's stress response.

Seems Lamarckian enough. I understand that there would need to then be a mechanism for inheriting these mutations. Which, since bacteria exchange genes, is sort of like it.

A few problems with this analysis:

- If there were any Lamarckian evolution in evidence, biologists would be on it like transcription complexes on a DNA strand in order to increase their fitness for the Nobel prize.

- The mutated genes are inherited, with or without gene exchange happening.

Contrary to the established view, soft inheritance is common. Variations acquired during an individual’s lifetime can be passed on through epigenetic, behavioral and symbolic[clarification needed] inheritance. They can affect the rate and direction of evolution by introducing additional foci for selection, by revealing cryptic genetic variation, and by enhancing the generation of local genetic variations. Moreover, under conditions of stress, epigenetic control mechanisms affect genomic re-patterning, which can lead to saltational changes.

I'm less making an argument than being open to a conjunction of ideas that seem to point in a direction.

I realize that the following is unfounded, but like Einstein's "God doesn't play dice", I have the following intuition:

There is some mechanism by which learning can couch effects in the body that can be passed on. YMMV. Actually, my intuition is more along the lines of: representation (mind) can redound on the body at levels below that which we can perceive directly. Inheritance of those effects is not something that I usually consider. I am quite aware that my intuition could be wrong. But it is a guiding principle for me, personally. When I see studies that hint at mechanisms which could be exploited by this tendency I "light up".

Contrary to the established view, soft inheritance is common. Variations acquired during an individual’s lifetime can be passed on through epigenetic, behavioral and symbolic[clarification needed] inheritance. They can affect the rate and direction of evolution by introducing additional foci for selection, by revealing cryptic genetic variation, and by enhancing the generation of local genetic variations. Moreover, under conditions of stress, epigenetic control mechanisms affect genomic re-patterning, which can lead to saltational changes.

I'm less making an argument than being open to a conjunction of ideas that seem to point in a direction.

I realize that the following is unfounded, but like Einstein's "God doesn't play dice", I have the following intuition:

There is some mechanism by which learning can couch effects in the body that can be passed on. YMMV. Actually, my intuition is more along the lines of: representation (mind) can redound on the body at levels below that which we can perceive directly. Inheritance of those effects is not something that I usually consider. I am quite aware that my intuition could be wrong. But it is a guiding principle for me, personally. When I see studies that hint at mechanisms which could be exploited by this tendency I "light up".

This is not epigenetic, nor, obviously, is it behavioral. Bacteria were selected for who were placed stress-related genes in regions with high mutation rates so as to increase the probability of beneficial mutations. Nothing soft, nor unique, about this.

Elementary, my dear Darwin.

Your statement about your mind-body relationship may be a guiding principle for you, but unless you can affect your sperm, I don't see how this can be transmitted to your children, i.e. in a Lamarkian fashion.

It's so cool that natural selection can search the ENTIRE design space spanned by variation in parallel, including going meta. Which is what is going on when evolution selects for designs that can more easily evolve. You're selecting not for first-order things like disease resistance etc, but for highly abstract high-order things like "is structured in such a way that subsequent evolution is more likely to produce fit variants".

So. Cool.

Yeah, its not a subject that gets much press.

One could idly wonder just how far it can go. Can we be certain for instance that entire taxa (species probably) can't control and regulate their adaptivity? Could there be biophysical features which exist for this purpose? How 'smart' is it?

Watching videos of complex biochemical processes taking place like this, it's amazing that it works at all. Fascinating stuff!

Absolutely. I'm not a molecular biologist, although I'm gradually learning more about it through my job. The more I learn about cells though, the more incredible it seems, not that they go wrong occasionally but that they work at all. Don't even get me started on developmental biology - that stuff just blows my mind!

Results like this could, properly publicized, go a long way toward easing the tensions between mainstream science and the evolution-rejecting / Intelligent Design crowd. The doubters (quite reasonably, in my estimation) can't swallow that pure random chance is responsible for all of life. This speaks to those doubts without need for non-science alternatives. Successful organisms appear to load the evolutionary dice in their favor.

And though this mechanism may not be strictly Lamarckian, others are: there is the recent evidence of the heritability of DNA methylation patterns (epigenetics), and of course, the long-known exchange of plasmids among bacteria. None of these mechanisms is Darwinian, and all could give an organism an evolutionary advantage over their Darwin-bound competitors. One would therefore expect to find more and more examples of not-entirely-random ways to evolve.

Darwin is to biology what Newton is to physics: a good start, but not the whole story. Rather than circling the wagons around Darwin to defend him from the ignorant fundamentalist savages, we should spin his shortcomings as pointing the way to improving our knowledge of how evolution really works.

Results like this could, properly publicized, go a long way toward easing the tensions between mainstream science and the evolution-rejecting / Intelligent Design crowd. The doubters (quite reasonably, in my estimation) can't swallow that pure random chance is responsible for all of life. This speaks to those doubts without need for non-science alternatives. Successful organisms appear to load the evolutionary dice in their favor.

I'd think it is a good example more for how it demonstrates the way in which only some parts of morphospace are explored, a 'reverse' copying enzyme would be possible, but investment means it will never happen because even the slightly less effective backwards readign kludge of the existing copying mechanism is probably vastly better than any de novo mechanism would be, having had gigayears of evolution behind it already. After all, it is still random chance, nothing DIRECTS the mutations, some are just more likely than others, and not even necessarily good ones more than bad ones.

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And though this mechanism may not be strictly Lamarckian, others are: there is the recent evidence of the heritability of DNA methylation patterns (epigenetics), and of course, the long-known exchange of plasmids among bacteria. None of these mechanisms is Darwinian, and all could give an organism an evolutionary advantage over their Darwin-bound competitors. One would therefore expect to find more and more examples of not-entirely-random ways to evolve.

Most plasmid-exchange is very much similar to sex though. It happens between closely related organisms. I'd also reflect on how hard it is to define the term 'species' in the context of bacteria. Its a lot more like sex than it is like inheritance of acquired characteristics, which it is not. So I see no resemblance to Lamark's theory there.

Epigenetics, for all the hype it has gotten, still has not been shown to be passed on. Methylation is mostly wiped clean during meosis. It is by no means shown that it is a major factor, and it is certainly a much less major factor than Darwinian evolution.

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Darwin is to biology what Newton is to physics: a good start, but not the whole story. Rather than circling the wagons around Darwin to defend him from the ignorant fundamentalist savages, we should spin his shortcomings as pointing the way to improving our knowledge of how evolution really works.

Meh, Darwin's observations and hypotheses have actually proven to be quite thorough and accurate. There are of course things he didn't work out. He didn't anticipate EVERY variation in the speciation process, nor was he able to fully define all the possible variations in rates of evolution. Even so if you read Darwin you will probably have to change your mind, and recall that he wrote much more than just On the Origin of Species. Today we have a much deeper understanding of the mechanisms behind what Darwin observed, but the fundamental structure of his theory is not just 'largely intact', it has in fact stood the test of time virtually unscathed. The comparison to Newton, who's theories of motion have been entirely replaced by a much different model, is inapt. Yes, Newtonian mechanics produce good results under most circumstances, but they do so for no reasons that Newton put forward whatsoever.

methylation certainly can be inherited, genetic imprinting is based on it, for example.

jgershon,

Why do you state methylation or epigenetics are non-Darwinian? Did you mean non-Mendelian?

In my understanding of Darwinian evolution, any trait that can be inherited can have evolutionary pressure applied to it, be that genetic or epigenetic changes.

Nor do I see how the examples discussed somehow invalidate the concept of random effects as a driver of evolutionary change (together with selection), since the discussed nonrandom distribution of genes where they may or may not experience higher mutation rates is itself the result of a long evolutionary trial and error history...

Remember, anything we are looking at today is the result of a very long history. As example, consider the fact that CpG dinucleotides, the targets of DNA methylation, are severely under-represented in the genome, because the methyl-C is mutagenic - so most have been eliminated, and the only ones left are there because there is positive selection to keep them there - another example of very non-random patterns driven by random change...

methylation certainly can be inherited, genetic imprinting is based on it, for example.

Really? My reading is that there is VERY limited evidence of any kind of transmission of methylation states from either parent to the zygote. Methylation which happens AFTER conception is nothing more than somatic accomodation, there's nothing special about it and it has virtually nothing to do with the germ line. Clearly organisms react to their environment and clearly one way they accomodate is by adjusting methylation states, but this is no kind of news at all and has zip to do with inheritance.

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jgershon,

Why do you state methylation or epigenetics are non-Darwinian? Did you mean non-Mendelian?

In my understanding of Darwinian evolution, any trait that can be inherited can have evolutionary pressure applied to it, be that genetic or epigenetic changes.

Its not that simple actually. Lamarkian 'evolution' wouldn't work. You need discrete inheritable traits. IF methylation states were passed on from parents to children directly and represented discrete traits then yes, perhaps they would produce evolution.

The term is definitely not ungoogleable, even if the latter is not a universally accepted word...

Well, first of all, there are large questions about calling this inheritence in the same fashion as genetic inheritence. In general this is more of a regulation mechanism, and note that while it MAY be that which gene was inherited from which parent is effectively recorded by methylation states, silenced genes are STILL INHERITED, they aren't gone. Nor are they silenced in future generations, the same rules are applied with each generation. Can this process INFLUENCE evolution, yes, but it isn't a separate evolutionary pathway itself, despite what the Wikipedia article may seem to imply (you have to watch those).